Following residency training in pediatrics, which included extensive clinical research experience, I have completed a fellowship in pediatric hematology/oncology which included research experience in molecular biology. I am currently pursuing a career in basic science research. My clinical emphasis remains the treatment of childhood malignancies and my research endeavors compliment this interest. The long term goal of this proposal is to establish expertise in a research area in order to become an independent investigator. The project described in this application seeks to identify the importance of the extracellular matrix (ECM) protein Thrombospondin (TSP) in the establishment of malignancy. The project will develop experimental systems which will be useful in studying aspects of malignancy related to growth control, transformation and differentiation. The basis for the proposal includes a number of observations linking TSP to cellular proliferation and a recent laboratory finding that antisense inhibition of TSP in human squamous carcinoma cells results in a more differentiated and a less invasive phenotype. Molecular biologic techniques will be used to investigate four specific aims: (i) determine if NIH 3T3 cells transfected with a construct to allow over expression of human TSP demonstrate altered growth kinetics and diminished serum requirements in culture; (ii) determine if over expression of TSP is transforming; (iii) determine whether the induction of TSP is a necessary event for cellular proliferation; and (iv) determine whether over expression of TSP inhibits cellular differentiation. Should these studies define a role for TSP in the processes of cellular proliferation, transformation and differentiation, unique chemotherapeutic options involving the ECM may be advanced. The scientific environment and facilities provided by the University of Michigan medical school will facilitate the success of this project and my further career development.